Type 1 diabetes, a Th1 mediated autoimmune disease, resulting from poorly defined interactions between susceptibility genes, the environment, and the immune system. A feature of T cell-mediated autoimmune diseases, including type 1 diabetes, is a reduced capacity of antigen presenting cells (APC) to activate T cells. Low levels of activation may predispose to autoimmune because apoptotic death of autoreactive T cells or generation of regulatory T cell responses requires quantitatively highly levels of activation than are needed for T cell survival. We have defined an APC defect, the constitutive expression of the normally inducible cyclooxygenase, prostaglandin synthase 2 (PGS2), which is common to monocytes (MO) of subjects at risk for type 1 diabetes and macrophages (MP) of NOD and NODscid mice. We determined in congenic mice that an NOD gene in a defined region of chromosome 1 controls the PGS2 phenotype, but is not the PGS2 gene. PGS2 expression allows high-level production of inflammatory PG and contributes to defective APC function. Our natural history studies in humans demonstrate healthy controls express low levels of PGS2, whereas high levels are present; 1.) Early in life as infants with high-risk HLA genotypes, 2.) In high risk autoantibody positive subjects, and 3.) in 80% of type 1 diabetics. Preliminary studies of patients with other established autoimmune disease demonstrate similar aberrant PGS2 expression and suggest this MO defect may be common to autoimmunity. Furthermore, omega-3 fatty acids which reduce PG metabolism appear to reduce the risk for autoantibodies, suggesting the PGS2 defect is regulatory by dietary environment. PG production appears to play a major role in diabetes pathogenesis as treating NOD mice with drugs that block both PGS activity significantly reduces diabetes incidence. Ongoing prospective studies demonstrated 12/17 (71%) high risk subjects who progressed to diabetes expressed high levels of PGS2. Preliminary, risk analysis suggests MO PGS2 expression increases the chance of developing diabetes by approximately 40%. In order to further define the etiology of PGS2 expression and its role in type 1 diabetes pathogenesis we will address the following specific aims, 1.) determine whether MO PGS2 expression is a risk factor for developing autoantibodies and type 1 diabetes, and establish whether it is similarly expressed in other autoimmune diseases, 2.( Determine the NOD gene(s) encoded on chromosome 1 which contribute to abnormal PGS2 expression and 3.) establish whether PGS2 specific inhibitors and supplementation of dietary omega-3 fatty acids reduce disease in NOD mice. The overall goal is to establish the utility of PGS2 as risk factor for type 1 diabetes and as a potential target for human diabetes prevention trials.